Genetic traits, coupled with a Western diet and lifestyle, have made cardiometabolic disorders/metabolic syndrome (MetS) a growing global epidemic. Cardiometabolic syndrome refers to a cluster of cardiovascular risk factors that include central obesity, high blood pressure, impaired glucose tolerance, hyperglycemia and dyslipidemia. Dyslipidemia is a major modifiable risk factor leading to atherosclerotic and related cardiovascular diseases (CVD), the nation's number one killer.
Cardiovascular Disease
Cardiovascular disease affects one in three people in the United States during their lifetime, and accounts for nearly a third of the deaths that occur each year (Rosamond W, et al., Circulation, 115, e69-e171, (2007)). Cardiovascular diseases are defined as diseases which affect the heart or blood vessels
Statins are considered as first-line therapy for subjects at risk for CVD focusing predominantly on the reduction in low-density lipoprotein cholesterol (LDL-C or “bad cholesterol”), to recommended target levels. However statins have minimal effect in raising high-density lipoprotein cholesterol (HDL C or “good cholesterol”), now recognized as a major risk factor for developing cardiovascular disease. Treatment options to raise HDL-C are very limited and include Niaspan® (branded niacin) which is known to cause flushing and is reported to cause hepatic enzyme abnormalities, and Tricor® (branded fenofibrates) which causes a 40% increase in LDL C and significant increase in liver enzymes, hematological changes, gall stones, pancreatitis, as well as myopathy. Some treatment options lower plasma triglycerides but have a negligible effect on HDL-C (Lovaza®). Other treatment options increase HDL-C, but are less effective on triglycerides.
Others have tried to increase HDL C (good cholesterol) without deleteriously affecting LDL, TG, or causing hypertension, but have not been successful. For example, torcetrapib appeared to raise HDL levels, but had no effect on TGs and LDL. However, torcetrapib caused severe hypertension and high mortality in phase III trials. Despite advancements in lowering total cholesterol, lipid abnormalities as well as other severe negative side effects still prevail. Treatment gaps in the management of dyslipidemia, considered one of the top five major modifiable risk factors of CVD, represent critical unmet medical needs. While most treatment methods only target the intrinsic LDL-C synthesis in the liver, other treatments are needed to further reduce triglycerides while increasing HDL-C and not increasing LDL-C.
Neurodevelopmental and Neurodegenerative Disease
Neurodevelopmental and neurodegenerative diseases/disorders and neurological imbalance (in neurotransmitters) affect many people, and are defined as chronic progressive neuropathy characterized by selective and generally symmetrical loss of neurons in motor, sensory, or cognitive systems. One progressive neurodegenerative disorder, Alzheimer's disease (AD), is irreversible, and is characterized by gradual cognitive deterioration, changes in behavior and personality. These symptoms are related to neurochemical changes, neural death, and the breakdown of the inter-neural connections. Loss of short-term memory is often the first sign, followed by cognitive deficits involving multiple functions. Early stages of AD and mild cognitive impairment are characterized as milder forms of memory loss or cognitive impairment that could precede the onset of dementia and AD. Prevention of further cognitive decline in subjects with these possible precursor conditions is of paramount importance given that reversibility of AD is not possible.
It is estimated there are currently about 5.1 million people with Alzheimer's disease (AD) in the United States (Alzheimer's Association, 2007) and this number is expected to reach 13.2 million by 2050 (Hebert et al., 2003) Alzheimer's is ranked as the 7th leading cause of death in the US for people of all ages and the 5th for people aged 65 or older (National Center for Health Statistics, 2004). In Canada it is 280,000 people over 65 that are estimated to have AD, and over 750,000 are expected to have the disease by 2031 (Alzheimer Society of Canada, 2006). It is estimated to 10% of all North Americans over the age of 70 years have early stage AD or mild cognitive impairment.
Alzheimer's disease is characterized by two main pathological features of the brain: intracellular neurofibrillary tangles formed by abnormal protein τ (tau); and extracellular neuritic plaques formed by β-amyloid peptides (Aβ) (Kuo et al., 1996). The overproduction of Aβ42 is genetically induced but environmental risk factors are required to get fully symptomatic AD (Grant et al., 2002). Among these risk factors, low docosahexaenoic acid (DHA) is one of the most important dietary risk factor for AD (Morris et al., 2005). The reasons for the impact of DHA on learning and memory and the association with AD are unclear but could result from its loss in synapses (Montine et al., 2004), which are normally rich in DHA (Salem et al., 2001), where it is particularly important for postsynaptic transmission and neuroprotection (Bazan, 2003). Studies in animal models have consistently showed that brain n-3 fatty acid content is highly dependent on dietary intake and aging (Favrere et al., 2000; Youdim et al., 2000; Calon & Cole, 2007). However, some reports claim higher concentrations of DHA have a deleterious effect in neurological patients.
Omega-3 Fatty Acids and Inflammation
Several animal studies, has shown that increased DHA intake has been found to increase hippocampal acetycholine levels and its derivatives, neuroprotectin DI, which decreased cell death (Aid et al, 2005; Lukiw et al., 2005). A study conducted on aged mice showed that DHA intake improved memory performance (Lim et al. 2001). In another Alzheimer's disease mouse model, reduction in dietary DHA showed loss of postsynaptic proteins associated with increased oxidation, which was localized in the dendrites. However, when a group of DHA-restricted mice where given DHA, they showed signs that the DHA intake protected them against dendritic pathology, implying that DHA could be useful in preventing cognitive impairment in Alzheimer's Disease (Calon et al., 2004).
Several epidemiological studies have shown a protective effect associated with increased fish intake (a direct source of omega 3 fatty acids) against dementia and cognitive impairment decline (Kalmijin et al. 1997, Barberger-Gateau et al. 2002; Morris et al 2003). Recently, one large randomized double-blind placebo-controlled study found 1.6 g DHA and 0.7 EPA may be beneficial in reducing risk for AD (Freund-Levi et al, 2006). In addition, there is mounting evidence that dietary supplementation with Omega 3 fatty acids may be beneficial in different psychiatric conditions such as mood behaviour, depression and dementia (Bourre et al., 2005; Peet and Stokes, 2005; Stoll et al., 1999).
The anti-inflammatory effects of omega-3 fatty acids have been widely studied with positive results for several chronic inflammatory diseases. C-reactive protein (CRP) is a protein that increases dramatically during inflammatory processes and is commonly measured as a marker of inflammation. Greater intake of omega-3 polyunsaturated fatty acid is related to a lower prevalence of elevated CRP levels. Animal models of colitis indicate that fish oil, a natural source of omega 3 fatty acids, decreases colonic damage and inflammation. Fish oil supplements in subjects with IBD have shown to modulate levels of inflammatory mediators and may be beneficial for the induction and maintenance of remission in ulcerative colitis. In the management of RA and other inflammatory conditions, side effects limit the use of NSAIDs, such as salicylates, ibuprofen and naproxen. A clinical trial showed that 39 percent of subjects with RA supplemented with cod liver oil were able to reduce their daily NSAID requirement by greater than 30 percent. Omega-3 fatty acids have been used to reduce the risk for sudden death caused by cardiac arrhythmias.
Furthermore, omega-3 fatty acids have been shown to improve insulin sensitivity and glucose tolerance in normoglycemic men and in obese individuals. Omega-3 fatty acids have also been shown to improve insulin resistance in obese and non-obese subjects with an inflammatory phenotype. Lipid, glucose and insulin metabolism have been show to be improved in overweight hypertensive subjects through treatment with omega-3 fatty acids.
Omega-3 fatty acids can be obtained from marine organisms such as squid, fish, krill, etc. and are sold as dietary supplements. However, the uptake of omega-3 fatty acids by the body is not efficient and these raw oils contain other substances such a triglycerides and cholesterol which are known to cause deleterious side effects such as an increase in LDL-C. Certain fish oils have been developed as pharmaceutical-grade OM3-acid ethyl esters. One such OM3-acid ethyl ester is presently sold under the brand name Lovaza®. Studies have shown that Lovaza® can decrease plasma triglycerides levels in patients, however, Lovaza® has a negligible effect on raising good cholesterol (HDL-C). AMR101 is another ethyl ester form of OM3 fatty acids based on EPA with little or no DHA that is presently in clinical trials. AMR101 also appears to decrease triclycerides but also has a negligible effect on raising HDL-C.
A phospholipid composition of OM3 fatty acids has been disclosed in US 2004/0234587. This phospholipid composition has OM3 fatty acids esterified to the phospholipid. This phospholipid composition is reported to be at a concentration of about 40% phospholipids (w/w composition) and contains high concentrations of triglycerides (about 45%) and free fatty acids (about 15%). When tested in subjects, this composition demonstrated very little effect on lowering triglyceride plasma levels (less than 11% reduction).
Marine oil compositions comprising free fatty acids and lipids, including OM3 fatty acids and phospholipids, have been disclosed in WO 2000/23546, however the compositions do not disclose OM3 fatty acids esterified to diglycerol phosphate and have very high concentrations of triglycerides and free fatty acids, and for these reasons would not be expected to reduce triglycerides even to the level of the composition disclosed in US 2004/0234587, described above.
Therefore, new forms of omega-3 fatty acids are needed that are useful for treating or preventing disease. Described herein are novel concentrated therapeutic phospholipid compositions, as well as pharmaceutical compositions comprising same, and methods of their use.